Oral Apixaban For The Treatment of Acute

Venous Thromboembolism

Done by :Fatimah Al-Shehri

Pharm.D Candidate King Abdul-Aziz university.

Supervised by : Dr.Sherine Esmail. 

Clinical pharmacist .  Internal medicine/

Nephrology.              

                                                                                                       

August 29, 2013Agnelli G., Buller H.R., Cohen A., et al.N Engl J Med 2013; 369:799-808

Introduction to Apixaban :

Pharmacological class. Indications:(FDA & non-FDA ) Mechanism of action. Pharmacokinetics. Contraindications. Advantages and disadvantages comparing to warfarin .

Introduction : Apixaban: is an oral anticoagulant . pharmacological class: Factor Xa inhibitor. Uses : Labeled Uses(FDA approved):

1-Stroke prophylaxis. Systemic embolism prophylaxis in patients with non-valvular atrial fibrillation. In 28 December, 2012.

Unlabeled Uses(non-FDA approved):

1-To reduce the risk of recurrent DVT and/or PE (in patients

completing 6-12 months of standard anticoagulation for venous thromboembolism).

2- Postoperative DVT prophylaxis for arthroplasty of the knee.

3- Postoperative DVT prophylaxis for total hip replacement.

Mechanism of action :

Oral anticoagulants in the management of venous thromboembolismJohn N. Makaryus, Jonathan L. Halperin & Joe F. LauNature Reviews Cardiology 10, 397-409 (July 2013)doi:10.1038/nrcardio.2013.73

Introduction:pharmacokinetics:

Absorption:- The bioavailability is 50%.

-(C max) appear 3 to 4 hours.

-Apixaban is absorbed throughout the GIT with the distal small bowel and ascending colon contributing about 55% of apixaban absorption.

Distribution:Plasma protein binding in humans is 87%. The Vd is 21 liters.

Metabolism:Approximately 25% is recovered in urine and feces as metabolites. Apixaban is metabolized mainly via CYP3A4.

Elimination:Apixaban is eliminated in both urine and feces. Renal excretion accounts for about 27% of total clearance. Biliary and direct intestinal excretion contributes to elimination of apixaban in the feces.

Introduction: Contraindications:

Active pathological bleeding. Severe hypersensitivity reaction to Apixaban. Liver diseases. With other anticoagulants. Prosthetic valves. Mitral stenosis.

Introduction:Comparison between Apixaban and Warfarin :

Apixaban Warfarin Items:

INR monitoring is not required but kidney function test required.

Frequent monitoring of INR. Follow up.

less food and drug interaction.

Any food containing vitamin k should be taken

consistently ,interact with many drugs.

Food and drug interaction

Rapid. Slow Onset of action :

Twice daily. Once daily Doses frequency .

No antidote. Vitamin K Antidote.

Higher than warfarin. Less than apixaban. Costs.

Less side effects .(less bleeding ).

More side effects especially bleeding .

Side effects(bleeding).

Previous studies:

5407 patients undergoing total hip replacement. Population :

Apixaban 2.5 mg orally twice daily. Intervention:

Enoxaparin at a dose of 40 mg subcut every 24 hours Comparator:

The primary efficacy outcome was the composite of asymptomatic or symptomatic DVT,nonfatal PE, or death from any cause during the treatment period.

Outcomes:

60 days after the last dose Time:

1-Apixaban versus Enoxaparin for Thromboprophylaxis after Hip Replacement:

Among patients undergoing hip replacement, thromboprophylaxis with apixaban,as compared with enoxaparin, was associated with lower rates of venous thromboembolism, without increased bleeding.

N Engl J Med 2010;363:2487-98 ,december 23, 2010 vol. 363 no. 26

Previous studies:

6528 subjects with CHF or RF or other medical disorders and at least one additional risk factor for VT .

Population:

Apixaban at a dose of 2.5 mg twice daily for 30 days, Intervention:

Enoxaparin, subcut at a dose of 40 mg once daily for 6 to 14 days. Comparator:

The primary efficacy outcome was the 30-day composite of death related to VTE, PE , symptomatic DVT, or asymptomatic proximal-leg DVT , as detected with the use of systematic bilateral compression ultrasonography on day 30. The primary safety outcome was bleeding.

Outcomes :

5 YEARS. Time:

In medically ill patients, an extended course of thromboprophylaxis with apixaban was not superior to a shorter course with enoxaparin. Apixaban was associated with significantly more major bleeding events than was enoxaparin.

N Engl J Med 2011;365:2167-77.

2- Apixaban versus Enoxaparin for Thromboprophylaxis in Medically Ill Patients.

The Study of The Journal Club:

Agnelli G., Buller H.R., Cohen A., et al.N Engl J Med 2013; 369:799-808

Study overview: Aim of the study :to compare the efficacy and safety of apixaban with the

efficacy and safety of conventional therapy in patients with DVT,PE or both.

PICOT:

5395 patients with acute venous thromboembolism. Population:

Apixaban 10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months.

Intervention:

conventional therapy (subcut enoxaparin, followed by warfarin).

Control:

The primary efficacy outcome was recurrent symptomatic VTE or death related to VTE.

The primary safety outcomes were bleeding major bleeding +clinically relevent nonmajor bleeding .

Outcomes:

Mean Follow up period was 6 months).)From 2008-2012. Time:

Study overview : Null hypothesis: Apixaban would be inferior to

conventional therapy with respect of the primary outcomes .

Trial design: Randomized, double-blind ,double dummy trial.

Funding: (Funded by Pfizer and Bristol-Myers Squibb; ClinicalTrials.gov number, NCT00643201).

Method: Randomization : Usage of an interactive voice-response system and was stratified

according to the qualifying diagnosis of either:

1-Symptomatic proximal deep-vein thrombosis.

2- Symptomatic pulmonary embolism (with or

without deep-vein thrombosis).

Method:Allocation and blinding:

Enoxaparin injectionsand warfarin tablets + placebo Apixaban tablets.

- Enoxaparin :1 mg/kg every 12 hours for at least 5 days.- Warfarin begun concomitantly and continued for 6 months .

Apixaban tablets +placeboEnoxaparin injections and placebo warfarin tablets.

- 10 mg twice daiy for 7 days .- 5mg twice daily for 6 months.

Double blinded , double dummy study , used blinded INR monitoring with a point-of-care device that generated an encrypted code for INR results.

Methods :Inclusion criteria :

Patients were eligible for inclusion in the study if

they were:

- 18 years of age or older and had objectively

confirmed, symptomatic proximal deep-vein

thrombosis or pulmonary embolism (with or without

deep-vein thrombosis).

Methods :Exclusion criteria :

Active bleeding OR a high risk of bleeding. Contraindications to treatment with enoxaparin &warfarin. If they had cancer and long-term treatment with LMWH was

planned. If their DVT or PE was provoked in the absence of a persistent risk factor for recurrence. If < 6 months of anticoagulant treatment was planned. If they had another indication for long-term anticoagulation therapy,

dual antiplatelet therapy, treatment with aspirin at a dose of more than 165 mg daily, or treatment with potent inhibitors of cytochrome P-450 3A4.

Methods :Exclusion criteria :

If they had received more than two doses of a once-daily LMWH regimen, fondaparinux, or a vitamin K antagonist. more than three doses of a twice-daily LMWH regimen; or more than 36 hours of continuous intravenous heparin.

A hemoglobin level of < 9 mg/dl. A platelet count of <100,000 per cubic millimeter, A serum creatinine level of >2.5 mg/dl, or a calculated CrCl of < 25 ml/min.

Method: Statistical analysis: Intention to treat analysis . The 95% confidence interval for the relative risk was calculated with the use

of the Mantel–Haenszel method.

The 95% confidence interval for the difference in risk was calculated for the primary outcome with the use of the inverse-variance method.

Statistical testing for non-inferiority was performed with the method of Farrington and Manning.

Time-to-event curves were calculated with the Kaplan–Meier method

Results:

Primary efficacy and safety outcomes :

Results:Kaplan –Meier cumulative event risk .

Results :Kaplan –Meier cumulative event risk .

Primary efficacy and safety outcomes:

Results:

Adverse effects : The rates of adverse events, including elevations in liver-function tests, were similar in the two treatment groups .

Rates of adverse events :

Subgroup analysis:

Subgroup analysis :

Study Conclusion :

On the basis of the results of this study, together

with those of the Apixaban for the Extended

Treatment of Deep Vein Thrombosis and

Pulmonary Embolism trials , apixaban provided a

simple, effective, and safe regimen for the initial

and long-term treatment of venous thromboembolism.

Critical Appraisal of The Topic:

Validity :Comment: Yes/No Validity (is the study valid?)

1-Randomization:Randomization was preformed with the use of interactive voice response system.

Yes. 1-Were patients randomized to treatment groups?

Yes. 2-Were the treatment and the control groups similar at the

beginning of the trial ?

Comment: Yes/No: Validity (is the study valid?)

2-Allocation:

It was double dummy study.

Yes. Was the randomization concealed?

Baseline characteristics:

Baseline characteristics:

Validity :Comment: Yes/No Validity (is the study valid?)

3-Blinding: -Double blinded, double dummy

-Investigator ,patients all were blinded.

- 1-Were measures objective or were the patients and clinicians kept blind to which treatment was being

received? Who was blinded?

It wasn't mentioned how did they assess it.

No. 2-Compliance: was it assessed ,How?

Any indications for antiplatelet anticoagulant ,aspirinWere excluded.

Yes. 3-Co-intervenstion?were groups treated equally?

No contamination mentioned.

No. 4-Contamination: was it mentioned?

Validity:Comment: :Yes/No :Validity (is the study valid?)

Intension to treat analysis or not?

It was ITT. 1-Were all patients who entered the trial accounted for ? And were they analyzed in the groups to which they were

randomized?

Sponsor?

The steering committee, consisting of academic authors & authors who were employees of Pfizer, had final responsibility for the study design, oversight, & data verification &analyses.

It was funded by Bristol-Myers Squibb and Pfizer.

-

1-How was the study funded?

Results :

Comment: Yes/No: What are the study results?

the incidence of the adjudicated composite of recurrent symptomatic VTE, thromboembolism or death related to VTE.

- 1-What was the primary endpoint?

Each component of the primary efficacy outcome, as well as death from cardiovascular causes and death from any

cause. Symptomatic recurrent VTE with death from cardiovascular causes, with death from any cause, or with death related to venous thromboembolism plus major bleeding.

- 2-What was the secondary endpoint?

Results :Comments: Yes/No: What are the study

results?

For the primary outcome no statistical difference.

No. 3-Was there statistically significant difference between

the treatments?

No. 4-Was it clinically significant?

Results: How are the results expressed ? FOR MAJOR BLEEDING :

EER=(Events in E group/total in E-group)=15/2691= 0.005=(0.6 %). CER=(Events in C group/total in C group)=49/2704= 0.018(1.8 %). RR=EER/CER= (0.33) RRR=1-RR=(1-0.33)= (0.67) ARR=CER-EER=(1.2)

NNH=[100/ARR=100/ 1.2]=83

For every 83 patients treated by apixaban 1 of them will experience MAJOR BLEEDING .

Results:Kaplan –Meier cumulative event risk .

Results :Kaplan –Meier cumulative event risk .

Applicability:.

comment: Yes/No: How can we apply the study results to our patients?

Yes. 1 -Will the intervention (Apixaban) be feasible in my settings?

Patients criteria matches the Criteria of our patients.

Yes. 2-Were the patients in this study similar to my patients?

Applicability:

Comment: Yes/No: How can we apply the study results to our patients?

Benefits: less bleeding . Yes. 3-Will the potential benefits of treatments outweigh the potential harms of

treatment for my patients?

Its cost is more than warfarin but the benefits outweigh the cost.

High cost.

4-Potential costs (Cost effectiveness, direct vs. indirect costs ).

No monitoring of INR. No regular follow up is

needed. Better tolerated. Less drug and food interation.

Yes. 5-Will my patients prefer this intervention?

Costs :

Price in SR: Price in:$ Medication: 1mg (80 RS )2.5mg(110RS)3mg(125 RS )5mh(119 RS )

1 -Warfarin.

110mg (382 RS )

2-Dabigatran.

3-Rivaroxaban.

4 -Apixaban.

Over all Conclusion:

Limitations : This study was funded by Bristol-Myers Squibb and

Pfizer. Many of the authors were affiliated with or employed by Bristol-Myers Squibb, which introduces a potential for bias.

The compliance was mentioned but it wasn't assessed .

Over all conclusion:

Strength : Minimization of bias with the double-blind design. Identical follow-up of all patients. Central adjudication of all outcome events. Study execution was rigorous, with minimal loss to follow-up, few

patients withdrawing consent, good adherence to study medication, and well-managed warfarin therapy.